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    Summary
    EudraCT Number:2017-003377-34
    Sponsor's Protocol Code Number:54767414ALL2005
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-02-06
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2017-003377-34
    A.3Full title of the trial
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    A.4.1Sponsor's protocol code number54767414ALL2005
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/180/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJanssen-Cilag International N.V.
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 715242166
    B.5.5Fax number+31 715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code HuMax-CD38
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414 (Daratumumab)
    D.3.9.3Other descriptive nameHUMAX-CD38
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typehuman monoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    E.1.1.1Medical condition in easily understood language
    Blood or bone cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066109
    E.1.2Term Precursor B-lymphoblastic leukemia acute
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066110
    E.1.2Term T-cell lymphoblastic leukemia acute
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in relapsed/refractory B-cell ALL and T-cell ALL as measured by the complete response (CR) rate.
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of daratumumab in addition to standard chemotherapy, including ORR, relapse-free survival (RFS), EFS, and OS in pediatric and young adult subjects with B-cell and T-cell ALL, and minimal residual disease (MRD) negative rate in subjects with B-cell and T-cell ALL
    - To assess the safety and tolerability of daratumumab in addition to standard chemotherapy in pediatric and young adult subjects with B-cell and T-cell ALL
    - To assess the PK of daratumumab in pediatric and young adult subjects with B-cell and T-cell ALL
    - To assess daratumumab immunogenicity in pediatric and young adult subjects with B-cell ALL and T-cell ALL
    - To assess daratumumab concentration in cerebrospinal fluid (CSF)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential subject must satisfy all the following criteria to be enrolled in the study:
    1. ≥1 and ≤30 years of age
    2. Documented ALL or LL as defined by the criteria below:
    a) B-cell cohort:
    Stage 1:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in second or greater relapse or refractory to 2 prior induction
    regimens with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in second or greater relapse or refractory to 2 prior induction
    regimens and biopsy proven and with evidence of measurable disease
    by radiologic criteria and aged 1 to 30 years
    b) T-cell cohort:
    Stage 1:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to <18 years
    Stage 2:
    - ALL in first relapse or refractory to 1 prior induction/consolidation
    regimen with ≥5% blasts in the bone marrow and aged 1 to 30 years
    - LL in first relapse or refractory to 1 prior induction/consolidation
    regimen biopsy proven and with evidence of measurable disease by
    radiologic criteria and aged 1 to 30 years
    3. Performance status ≥70 by Lansky scale (for subjects <16 years of age) or Karnofsky scale (for subjects ≥16 years of age)
    4. Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:
    a. Hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion is permitted)
    b. Platelet count ≥10 × 109/L (prior platelet transfusion is permitted)
    5. Adequate renal function defined as normal serum creatinine for the subject’s age or creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥70 mL/min/1.73 m2 prior to enrollment (see Attachment 3).
    6. Adequate liver function prior to enrollment defined as:
    a. Alanine aminotransferase level ≤2.5x the upper limit of normal (ULN)
    b. Aspartate aminotransferase level ≤2.5xULN, and
    c. Total bilirubin ≤2x ULN or direct bilirubin level ≤2.0xULN
    7. Female subjects of childbearing potential (defined as post-menarchal and sexually active until becoming post menopausal unless permanently sterile) must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose
    interruptions, and for 12 months after the last dose of any component of the treatment regimen. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
    Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject. Birth control methods must
    include one highly effective method of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks
    prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
    8. During the study and for 12 months after receiving the last dose of any component of the treatment regimen, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
    9. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 6 months after discontinuing study treatment (even after a successful vasectomy)
    10. Male subjects of reproductive potential must not donate sperm during the study or for 6 months after the last dose of study treatment
    11. The informed consent form (ICF) must be signed by a legally authorized representative or by the subject if at legal age of consent indicating understanding of the purpose of, and procedures required for, the study and willingness to participate in the study. Assent is also required of children capable of understanding the nature of the study according to country-specific or site-specific standards
    12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
    E.4Principal exclusion criteria
    1.Received an allogeneic hematopoietic transplant within 3 months of screening
    2.Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease of Grade 2 or higher
    3.Received immunosuppression post hematopoietic transplant within 1 month of study entry
    4.Philadelphia chromosome positive(Ph+)B-cell ALL eligible for tyrosine kinase inhibitor therapy
    5.Has either of the following:
    a.Evidence of dyspnea at rest or oxygen saturation ≤94%
    b.Known moderate or severe persistent asthma within the past 2 years,or uncontrolled asthma of any classification.
    Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma may participate in the study
    6.Down syndrome,juvenile myelomonocytic leukemia,Fanconi anemia,Kostmann syndrome,Shwachman syndrome,or any other known bone marrow failure syndrome
    7.Prior exposure to daratumumab or other anti-CD38 therapies
    8.Prior cancer immunotherapy (ie,CAR-T,inotuzumab)within 4 weeks prior to enrollment or blinatumomab within 2weeks prior to enrollment
    9.For subjects with T-cell ALL/LL only:prior cumulative anthracycline exposure must not exceed 400 mg/m^2 of doxorubicin or equivalent
    10.Subject is:
    -known to be seropositive for HIV
    -seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).Subjects with resolved infection (ie,subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc]and/or antibodies to hepatitis B surface antigen [Anti-HBs])must be screened using realtime polymerase chain reaction (PCR) measurement of HBV DNA levels.Those who are PCR positive will be excluded. EXCEPTION:Subjects with serologic findings suggestive of HBV vaccination(Anti-HBs positivity as the only serologic marker)AND a known history of prior HBV vaccination,do not need to be tested for HBV DNA by PCR
    -known to be seropositive for hepatitis C(except in the setting of a sustained virologic response [SVR],defined as aviremia at least 12weeks after completion of antiviral therapy)
    11.Screening 12-lead electrocardiogram (ECG)showing a baseline QT interval >470msec or Grade 3 or higher cardiac disorders(according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03)
    12.Known allergies,hypersensitivity,or intolerance to mannitol,glucocorticoid,methotrexate,vincristine,mAb (IRR is not considered hypersensitivity)or human proteins,or their excipients (refer to respective package inserts and Investigator's Brochure),or known sensitivity to mammalian-derived products.For subjects with Tcell ALL/LL only,known allergies to doxorubicin,cytarabine,cyclophosphamide,or 6-mercaptopurine
    13.Received an investigational drug,was vaccinated with live attenuated vaccines,or used an invasive investigational medical device within 4weeks before the planned first dose of study drug,or is currently being treated in an investigational study
    14.Pregnant,breastfeeding,or planning to become pregnant while enrolled in this study or within 12months after the last dose of any component of the treatment regimen
    15.Plans to father a child while enrolled in this study or within 6months after the last dose of any component of the treatment regimen
    16.Subject has any concurrent medical or psychiatric condition or disease (eg,active systemic infection,uncontrolled diabetes,acute diffuse infiltrative pulmonary disease)that is likely to interfere with the study procedures or results,or that in the opinion of the investigator,would constitute a hazard for participating in this study
    17.Major surgery within 2 weeks before screening,or will not have fully recovered from surgery,or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration
    Note:Subjects with planned surgical procedures to be conducted under local anesthesia may participate
    18.Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder).Subject has any condition for which,in the opinion of the investigator, participation would not be in the best interest of the subject (eg,compromise the well-being) or that could prevent,
    limit, or confound the protocol-specified assessments.Subject is taking any prohibited medications listed in Section 8. Subject is not affiliated to,or a beneficiary of,asocial security category,per local regulatory requirements,if applicable
    19.Subject has B-cell ALL/LL or T-cell ALL/LL and is eligible for treatment with an approved agent (eg,blinatumomab, nelarabine)
    20.Subjects with infant leukemia (defined as under 1 year old at the time of initial diagnosis)These subjects will not be eligible for this study,even if they are greater than 1 year old at the time of relapse.
    E.5 End points
    E.5.1Primary end point(s)
    1. Complete response (CR) rate
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Within 2 cycles of therapy for B-cell ALL and at the end of Cycle 1 for T-cell ALL
    E.5.2Secondary end point(s)
    1. Overall response rate (ORR)
    2. Event-free survival (EFS)
    3. Relapse-free survival (RFS)
    4. Overall survival (OS)
    5. Minimal residual disease (MRD) negative rate
    6. Proportion of subjects who receive an allogeneic Hematopoietic stem cell transplant (HSCT) after treatment with daratumumab
    7. PK of daratumumab in pediatric and young adult subjects (Cmax and Cmin)
    8. Daratumumab immunogenicity incidence in pediatric and young adult subjects with B-cell T-cell ALL/LL
    9. Concentration of daratumumab in Cerebrospinal fluid (CSF)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Time from date of first treatment to first documented treatment failure or date of relapse from CR or death due to any cause, whichever occurs first
    2.Time from CR to relapse from CR or death due to any cause, whichever
    occurs first
    3.Time from date of first treatment to date of death due to any cause
    4.End of both Cycle (C)1 &C2 for T-cell cohort and Day (D)28 of every other cycle from C4 until CR for B-ALL/LL
    5.End of both C1,2
    6.B-cell cohort-Predose & at end of infusion on D1 of C1,2,3,6,9, EoT, follow-up
    T-cell cohort-Predose and at end of infusion at C1D1, C2D1,22, EoT, follow-up
    7.B cohort-Predose on D1 of C1,2,6,9, EoT, follow-up
    T cohort-Predose on D1 of C1,2, EoT, follow-up
    8.B cohort-Predose on D1 of C1,2,3,4,6,9
    T cohort-Predose on C1D1,15, C2D2,15
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA28
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Germany
    Israel
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will end 1 year after the last subject has initiated treatment. A futility analysis will be performed after Stage 1 of the study and could result in the trial ending prior to this if specific, protocol-defined efficacy events are not met.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 54
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children aged 1 year -18 years
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 69
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-11
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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